Antibiotic formulation and use for drug resistant infections

Abstract

A liposomal aminoglycoside formulation comprising a neutral lipid, a negatively charged lipids and a sterol. The formulation contains unilamellar vesicles having an average size below 100 nm. A process of making liposomes containing an aminoglycoside is provided where the hydration temperature is significantly below the transition temperature of the formulation. A method for the treatment of drug susceptible and drug resistant bacteria.

What is claimed is: 
     
       1. A method of treating a bacterial infection in a patient comprising the delivery to the patient of an effective amount of liposomes consisting essentially of an encapsulated aminoglycoside, wherein the liposomes are comprised of cholesterol, a neutral amphiphilic lipid and a negatively charged amphiphilic lipid, wherein said negatively charged amphiphilic lipid is less than 20% of the total lipid, wherein the aminoglyoside to total lipid molar ratio is from 1:9 to 1:3 and wherein the liposomes consist of unilamellar vesicles having an average size of less than 100 nm. 
     
     
       2. The method of claim 1 wherein the negatively charged amphiphilic lipid is 5% or less of the total lipid. 
     
     
       3. The method of claim 1 wherein the neutral amphiphilic lipid, cholesterol and negatively charged amphiphilic lipid are in a molar ratio of about 2:1:0.1. 
     
     
       4. The method of claim 1 wherein the neutral and negatively charged amphiphilic lipids are saturated. 
     
     
       5. The method of claim 4 wherein the saturated neutral and negatively charged amphiphilic lipids are phospholipids. 
     
     
       6. The method of claim 5 wherein the saturated neutral phospholipid is selected from the group consisting of hydrogenated egg phosphatidylcholine (HEPC), dimyristoylphosphatidylcholine (DMPC), hydrogenated soy phosphatidylcholine (HSPC), distearoyl phosphatidylcholine (DSPC), and dipalmitoyl phosphatidylcholine (DPPC). 
     
     
       7. The method of claim 5 wherein the saturated neutral phospholipid is hydrogenated soy phosphatidylcholine (HSPC). 
     
     
       8. The method of claim 5 wherein the saturated negatively charged phospholipid is selected from the group consisting of hydrogenated soy phosphatidylglycerol (HSPG), hydrogenated egg phosphatidylglycerol (HEPG), distearyolphosphatidylglycerol (DSPG), dimyristoyl phosphatidylglycerol (DMPG), and dilaurylphosphatidylglycerol (DLPG). 
     
     
       9. The method of claim 5 wherein the saturated negatively charged phospholipid is distearoylphosphatidylglycerol (DSPG). 
     
     
       10. The method of claim 1 wherein the bacterial infection is caused by Gram negative bacteria. 
     
     
       11. The method of claim 1 wherein the bacterial infection is caused by Gram positive bacteria. 
     
     
       12. The method of claim 10 wherein said Gram negative bacteria are members of the genus Pseudomonas. 
     
     
       13. The method of claim 11 wherein said Gram positive bacteria are members of the genus Mycobacterium. 
     
     
       14. The method of claim 13 wherein said Mycobacterium are selected from the species consisting of Mycobacterium tuberculosis, Mycobacterium leprae, Mycobacterium intracellulare, Mycobacterium smegmatis, Mycobacterium bovis, Mycobacterium kansasii, Mycobacterium avium, Mycobacterium scrocalcium, and Mycobacterium africanum. 
     
     
       15. The method of claim 13 wherein said Mycobacterium is Mycobacterium avium. 
     
     
       16. The method of claim 13 wherein said Mycobacterium is Mycobacterium tuberculosis. 
     
     
       17. The method of claim 14 wherein said Mycobacterium is Mycobacterium avium--intracellulare complex (MAC). 
     
     
       18. The method of claim 1 wherein said aminoglycoside is selected from the group consisting of streptomycin, neomycin, kanamycin, gentamicin, tobramycin, sisomicin, amikacin, and netilmicin. 
     
     
       19. The method of claim 1 wherein said aminoglycoside is amikacin. 
     
     
       20. The method of claim 3 wherein said aminoglycoside is selected from the group consisting of streptomycin, neomycin, kanamycin, gentamicin, tobramycin, sisomicin, amikacin, and netilmicin. 
     
     
       21. The method of claim 3 wherein said aminoglycoside is amikacin. 
     
     
       22. The method of claim 15 wherein said aminoglycoside is selected from the group consisting of streptomycin, neomycin, kanamycin, gentamicin, tobramycin, sisomicin, amikacin, and netilmicin. 
     
     
       23. The method of claim 15 wherein said aminoglycoside is amikacin. 
     
     
       24. The method of claim 16 wherein said aminoglycoside is selected from the group consisting of streptomycin, neomycin, kanamycin, gentamicin, tobramycin, sisomicin, amikacin, and netilmicin. 
     
     
       25. The method of claim 16 wherein said aminoglycoside is amikacin. 
     
     
       26. The method of claim 17 wherein said aminoglycoside is selected from the group consisting of streptomycin, neomycin, kanamycin, gentamicin, tobramycin, sisomicin, amikacin, and netilmicin. 
     
     
       27. The method of claim 17 wherein said aminoglycoside is amikacin. 
     
     
       28. A method of inhibiting bacterial growth in a patient comprising the delivery to the patient of an effective amount of liposomes consisting essentially of an encapsulated aminoglycoside, wherein the liposomes are comprised of cholesterol, a neutral amphiphilic lipid and a negatively charged amphiphilic lipid, wherein the aminoglycoside to the total lipid molar ratio is from 1:9 to 1:3, wherein the negatively charged amphiphilic lipid is less than 20% of the total lipid and wherein said liposomes consist of unilamellar vesicles having an average size of less than 100 mm. 
     
     
       29. A method of treating a bacterial infection in a patient comprising the delivery to the patient of an effective amount of liposomes consisting essentially of encapsulated amikacin, wherein the liposomes are comprised of cholesterol, HSPC, and DSPG, wherein the amikacin to total lipid molar ratio is from 1:9 to 1:3 and wherein said liposomes consist of unilamellar vesicles having an average size of less than 100 nm. 
     
     
       30. The method of claim 29 wherein DSPG is 5% or less of the total lipid. 
     
     
       31. The method of claim 29 wherein HSPC:cholesterol:DSPG are in a molar ratio of about 2:1:0.1.